ad a) If a patient has responded to an antipsychotic in the past this could be a predictor that he will respond to it again.

Ad b) Similarly, side-effects experienced in the past might be avoided by choosing another antipsychotic.
Ad c) If it is clear that a patient will receive a depot for maintenance treatment, choosing the oral form of the same drug can facilitate the later transition.

Ad d) Antipsychotics differ largely in side-effects (e.g. Leucht et al., 2013a; Leucht et al., 2009b). This also applies to long-acting injectable formulations of antipsychotics (McEvoy et al., 2014), which have side-effect profiles that closely resemble their oral versions (Fleischhacker et al., 2014). Table 1 provides an overview of the side-effect profiles of second-generation antipsychotic and the two prototypal first-generation antipsychotics haloperidol and chlorpromazine that might be used for the selection (Table 1).

Ad e) Meta-analyses found that some antipsychotics (clozapine, amisulpride, olanzapine, risperidone, (zotepine, paliperidone)) are somewhat more efficacious than others (Davis et al., 2003; Geddes et al., 2000; Leucht et al., 2009b). We highlight that apart from clozapine, which is restricted to treatment resistant patients, the superiorities were small and overall smaller than differences in the major side-effects.

Ad f) A variety of antipsychotics with different profiles is available. Some patients may want to avoid weight gain, others EPS or sexual side-effects, and again others might even want an only slightly more efficacious drug, irrespective of side-effects. We, therefore, recommend involving patients in the decision where feasible. Involving patients in the decision making progress is simply good clinical practice and may also improve compliance and long-term outcome – despite limited evidence there is at least one RCT suggesting positive effects on some outcomes (Hamann et al., 2007; Hamann et al., 2003).

Ad g) New antipsychotics are generally more expensive than older ones, but medication cost will differ between countries (e.g. newer antipsychotics become generic and usually cheaper at some stage) and settings. Therefore, no general statement can be made, but it certainly is a criterion for choice, as well.

2. Patients should be started on monotherapy with one drug (A)

﻿Justification:

Polypharmacy can be associated with more side-effects and drug-drug interactions (Fleischhacker and Uchida, 2014). If two antipsychotics are started simultaneously it is difficult to disentangle which drug was efficacious, making it difficult to stop one of them once the patient has responded. Similarly, if side effects emerge, it is unclear, which medication or dose may need to be changed. Moreover, non-adherence is an enormous problem in schizophrenia, and the more drugs patients receive the more difficult it could be to comply with the regimen. There is no randomized evidence supporting the immediate start of combination therapy apart from a meta-analysis of Chinese trials that was mainly based on combinations of clozapine with other antipsychotics (Correll et al., 2009b), but in most countries clozapine is restricted to refractory patients. The rationale of combining antipsychotics is also limited by the fact that they all have the same main putative mechanism of action for psychosis, which is dopamine blockade (Goodwin et al., 2009).

3. Factors that need to be checked before non-response is assumed

a) Is the underlying psychiatric diagnosis correct and have psychiatric comorbidities, including substance abuse, as well as somatic comorbidities or somatic causes been adequately excluded? (C)
b) Have ongoing environmental or psychological stressors as a cause of non-response been excluded? (C)
c) Has response been measured objectively and quantitatively? (C)
d) Do side effects mask a response, mimic non-response? (C)
e) Has a sufficient dose been given? (A)
f) Was treatment given for an adequate duration (change of treatment only if less than minimal response despite at least 2-4 weeks with full dose)? (A)
g) Has compliance been checked/optimized? Optimize compliance-transparency by obtaining antipsychotic plasma-levels (C), or use of liquids or rapidly-dissolving tablets (especially in inpatients (C)), or depot drug. (B)
h) Has an adequate plasma level been reached? If not (and therapeutic windows are available), check for cytochrome-P-450 polymorphism, effect of smoking or drug-drug interactions. (C)

Justification:

Ad a) For example, a psychotic depression/mania or severe personality disturbances can be difficult to distinguish from schizophrenia. Similarly, many neuropsychiatric disorders such as encephalitis, neurosyphilis can mimick schizophrenia and heavy cannabis or alcohol abuse can explain non-response, as well.

Ad c) Unfortunately, the assessment of response to antipsychotic medication often remains subjective and qualitative, resulting in ambiguous judgments. Response should be assessed in a standard fashion, ideally both qualitatively as well quantitatively using validated psychometric instruments (e.g. at least the CGI or the 8 PANSS items on which the remission criteria by Andreasen et al., 2005 are based).

Ad d) For example, akathisia can be confused with psychotic agitation or parkinsonism can mimic negative symptoms. Such confounding factors need to be ruled out and addressed before non-response is established.

Ad e) It should be checked whether the patient has received a dose within the recommended dose range. If possible, a dose at the upper limit of these ranges should be given before non-response is determined. Guidelines differ slightly in their recommendations. The numbers presented below are according to those of the International Consensus Study on Antipsychotic Dose (Gardner et al., 2010). Equivalent dose tables based on various methods have also been published elsewhere (Leucht et al., 2015a; Leucht et al., 2014). We emphasize that the optimum doses for newer antipsychotics have been established by appropriate dose finding studies, while much less is known about the optimum doses of older antipsychotics, including haloperidol one of the few older drugs for which a real dose/response study exists (Zimbroff et al., 1997). For haloperidol, for example, a Cochrane review (Waraich et al., 2002) concluded that doses up to 7.5 mg/day should usually be sufficient in uncomplicated patients with schizophrenia. While there is evidence for some of these medications that doses below this range (e.g. risperidone 1 mg/d; aripiprazole 2 mg/d) are ineffective; there is no good randomized evidence that doses higher than these ranges show a further increase in response (also see paragraph on increasing the dose in case of non-response below). The main concern on the higher end is an increase in side-effects and cost.

All doses are presented in mg/day. Target doses were defined as the “doses considered to be effective and acceptably tolerated by most patients”, and maximum doses as the “dose at which no further benefits are expected if exceeded or at which when exceeded the harms usually outweigh the benefits in patients”. N.i. = not indicated. Please note that for first-episode patients and elderly patients usually lower doses are sufficient (see respective passage of this algorithm).

All doses are presented in mg. Respondents were asked to indicate their usual initial intramuscular dose, the dose range per injection, and the maximum intramuscular dose per 24 hours for the reference case. Range of doses/injection reflects the median lower and upper doses of ranges recommended. The reference case was an adult man with DSM-IV schizophrenia not treated for 2 weeks, presenting with delusions, auditory hallucinations, agitation, poor cooperation, threatening behavior, and who is refusing oral medications (modified from Gardner et al. 2010)

Respondents were asked to indicate their usual dosing interval, initial dose, target dose range, and maximum dose for the reference case. The reference case was a moderately symptomatic adult man with DSM-IV schizophrenia, not considered treatment-refractory with ≥2 years of antipsychotic treatment with poor treatment adherence to oral antipsychotics. Target dose range reflects the median lower and upper doses of the ranges recommended (modified from Gardner et al. 2010)

Ad f) The onset of response to treatment of individual patients is highly variable. Nevertheless, recent meta-analyses rejected the long-held hypothesis that there is a general ‘delay of onset of action’ of antipsychotic drugs of several weeks. The largest part of the drug effect occurred in the first week and got consistently smaller thereafter (Agid et al., 2003; Leucht et al., 2005). An early response pattern has also been shown for clozapine (Sherwood et al., 2012). Moreover, several studies suggested that patients who had not improved at two weeks were unlikely to respond to the same antipsychotic at a later stage (Ascher-Svanum et al., 2007; Chang et al., 2006; Correll et al., 2003; Jager et al., 2009; Kinon et al., 2008a; Leucht et al., 2007a; Leucht et al., 2008; Lin et al., 2007). While one study (Lambert et al., 2009) was not consistent with the other evidence, and while analyses in first-episode populations were also not consistent with the findings of multiple-episode populations (Gallego et al., 2011; Schennach-Wolff et al., 2010), a diagnostic test meta-analysis of 32 trials confirmed the predictive value of less than 20% PANSS/BPRS total score reduction at two weeks as a predictor of non-response at six weeks (Samara et al., 2015). Still, little evidence is available that switching, a major dose increase or combination treatment is effective (see below). We, therefore, recommend, at least in multi-episode patients, unless the clinical situation demands an earlier intervention, that a 2- to 4-week antipsychotic trial at a therapeutic dose in the upper dose range is appropriate before considering a specific antipsychotic ineffective for a patient. The notion “at a therapeutic dose in the upper dose range” is important, because some drugs, in particular clozapine, require slow titration. We nevertheless feel that previous claims to try clozapine for at least six months were mainly based on an uncontrolled case series (Meltzer et al., 1989) although continued treatment with clozapine beyond 4 weeks leads to an increased likelikhood of achieving response (Kane et al., 2001).

Ad g) In the case of suspected compliance problems these can be addressed by switching to liquid medication or rapidly dissolving tablets and/or supervised drug intake. Depot medication is another option (see paragraph on depot antipsychotics below). Plasma-levels can help in determining non-compliance and in monitoring compliance. The use and the determination of a patient’s Cytochrom-P-450 status (Muller et al., 2013) can also be useful in certain circumstances as detailed below.

Ad h) The relationship between plasma-levels and response to antipsychotic drugs is not strong enough to recommend the titration into therapeutic concentration windows. Hiemke et al., 2011 present an overview of the levels for different psychotropic drugs. It might be most useful for clozapine (Buchanan et al., 2010). If available, antipsychotic plasma level measurements can be indicated in the following situations:

– Suspicion of non-compliance

– Lack of response in spite of taking usually sufficient doses to rule out ultra-rapid excessive metabolization of the antipsychotic due to a polymorphism of the cytochrom-P450 enzyme system (Muller et al., 2013).

– Pronounced side effects despite the administration of a usual dose to rule out „poor metabolizers“ due to too little production of cytochrom-P450 enzymes.

– The genetically determined metabolizer status, medication interactions, smoking, etc. which can also lead to elevated or lowered plasma levels via effects on the Cytochrom-P450 system.

4. Initial non-response: The antipsychotic may be switched (A-) or the dose may be increased beyond the officially indicated range (C). The evidence supporting both strategies is very limited. If the dose is increased, it should be decreased back to the original dose in case of lack of effect of the higher dose (C). If the drug is switched, choose an antipsychotic with a different receptor binding profile than the previous one (A-). Also consider the general selection criteria described above (see 1).

Justification:

The evidence for both strategies is limited with a certain advantage for switching.

a) Switching the drug (Leucht et al., 2015b): One trial found that when patients, who had at best minimally improved after two weeks treatment with risperidone, were switched to olanzapine, their outcome was significantly better than that of those who stayed on risperidone, but the difference was small (Kinon et al., 2010). In patients who had not responded to a four week trial of 20mg/day fluphenazine, Kinon et al., 1993 found no difference between a) continuation with fluphenazine 20mg/day (control group), b) dose increase to fluphenazine 80mg/day or switch to haloperidol 20mg/day.The limitation was the switch to a very similar high-potency antipsychotic (from fluphenazine to haloperidol, the study was conducted before more different newer drugs were available) and the fluphenazine dose in the run-in phase which is nowadays considered to be a high dose. Shalev et al., 1993 and Suzuki et al., 2007, randomized patients to three different antipsychotics. Non-responders were re-randomised to one of the two remaining two antipsychotics. If they failed to respond again they were switched to the remaining antipsychotic. At the end of both studies, the majority of participants had responded, but both studies had the major limitation of not having a control group that stayed on the initial drug to rule out that the improvement was simply an effect of time. In two small studies Hatta et al., 2011 randomised non-improvers to two weeks of treatment with risperidone/olanzapine to either staying on the same drug or switching to the other one. Switching did not lead to higher response rates, but the authors emphasize that the trials were underpowered. In a post hoc analysis of CATIE phase 1, patients taking olanzapine or risperidone before entering the trial stayed on treatment longer if they were assigned to stay on the same treatment (Essock et al., 2006). I.e. for these groups ‘sticking’ was better than ‘switching’. One reason might have been that some of the chronic patients in CATIE were relatively stable at baseline and might have been destabilized by a switch. In summary, the evidence for switching antipsychotics is limited, but stronger than that for dose increase (see next chapter).

A later CATIE phase provides suggestive information on how to choose a new antipsychotic when switching. Stroup et al., 2007 analyzed those 114 participants who had received perphenazine in CATIE phase 1, but discontinued it. Participants who were randomized to quetiapine or olanzapine in phase 2 stayed on the antipsychotic longer than those randomized to risperidone. A possible explanation is that because perphenazine and risperidone have similar receptor-binding profiles, switching from one to the other has little effect. Thus, if the antipsychotic drug is changed, it is reasonable to choose a compound with a different receptor-binding profile. This pragmatic recommendation is based on the underlying assumption that patients who have not responded to one drug might respond to or have less adverse effects on another drug with a very different pharmacologic profile. If there has been non-response to at least two antipsychotics, we recommend a trial of clozapine (See below).

b) Substantial dose increase: The aforementioned study by Kinon et al., 1993 showed no incremental efficacy of increasing fluphenazine 20mg/day to 80mg/day. McEvoy et al., 1991 randomized patients who had not responded to neuroleptic threshold doses of haloperidol (mean 2.3 mg/day) to either continuation of threshold doses or doses up to 10 times. The dose increase was not associated with better efficacy. Hatta et al., 2012 found no significant difference between switching to olanzapine and increasing the risperidone dose in two week non-improvers to risperidone (Hatta et al., 2012). Kinon et al., 2008b found no efficacy difference between 10mg/day, 20mg/day and 40mg/day olanzapine in patients with suboptimal response to previous treatment. 40mg/day olanzapine was only somewhat (but statistically significantly) better in a severely-ill subgroup. Two small RCTs did not find a superiority of high dose quetiapine (1200mg/day) compared to 800mg/day and 600mg/day (Honer et al., 2012; Lindenmayer et al., 2011). A meta-analysis of the currently available studies also showed no superiority of increasing the dose in non-responsive patients (Dold et al., 2015). Thus, the evidence supporting doses above the therapeutic ranges is scarce, but as there are so few RCTs more trials are clearly needed. Some individuals respond only to very high doses and such a history should be considered, these may be also ultra-rapid metabolizers. We strongly discourage excessive doses as a general strategy. It is very important that if a dose increase beyond the optimum doses was not effective, the dose is again reduced to previous levels. Patients should never be exposed to unnecessarily high doses of antipsychotic medication.

5. Drugs should be switched applying an “overlap and taper” or “cross-over” strategies, especially when switching from sedating to less sedating and from high affinity full dopamine antagonists to lower affinity dopamine antagonists or to a partial agonist (A).

Justification:

Different switch strategies have been used clinically, but only few have been compared head to head. “Stop-start” means that the original drug is stopped abruptly and the next one immediately started. “Cross-over” means that the original drug is gradually tapered while the dose of the next one is gradually increased. “Overlap and taper” means that the full dose of the original drug is maintained until the next one reaches its therapeutic dose. Only then is the original drug gradually tapered. Finally, in one study the original antipsychotic was tapered entirely and the next drug (olanzapine) was started only one week afterwards (Kinon et al., 2000). This strategy was slightly less efficacious and carries a risk of loss of efficacy and of rebound symptoms, but should theoretically be associated with the fewest side-effects. There are theoretical pros and cons of the other three strategies: “Stop-start” is fast, but there could be withdrawal effects from the discontinuation of the original antipsychotic and efficacy problems, as the following drug has not developed its full effects. In “cross-over” there may be drug-drug interactions and a point when no drug develops its full efficacy. “Overlap and taper” is the safest procedure efficacy-wise, but if antipsychotics have similar adverse effects, these could be additive, and sometimes patients might be doing better when they have the combination making it difficult to stop one drug. Initial studies of second-generation antipsychotics and an earlier meta-analysis (Remington et al., 2005) did not find significant differences between abrupt or gradual initiation of the new antipsychotic, or between abrupt or gradual discontinuation of the pre-switch antipsychotic (Remington et al., 2005). However, a recent, larger meta-analysis found that abrupt stopping of the prior antipsychotic and abrupt starting of the new antipsychotic were each associated with significantly greater all-cause discontinuation than gradual switches. Moreover, cross over and overlap and taper procedures were associated with significantly lower all-cause discontinuation rates than little or no overlapping strategies (Correll et al., 2011). The advantage of overlapping switches was strongest when switching to aripiprazole or ziprasidone. Although there were no differences in PANSS total scores between the switch strategies, patients were relatively stable and patients who dropped out were often not available for psychopathology ratings. Thus, if time allows and when a switch is performed to reduce adverse effects, we would recommend “cross-over” or “overlap and taper”. However, in acutely exacerbated patients or when speed of the switch is important, “stop-start” switching is also possible, especially when concomitant benzodiazepines can be used to mitigate any relevant rebound or withdrawal effects and when the initial drug has not been taken for more than two weeks. In addition, it must also be considered that these recommendations do not hold true for all drugs. For example clozapine needs to be titrated slowly. And when the original medication is a depot antipsychotic, it can simply be stopped because due to the long half-life it will take considerable time until it is washed out. Conversely, if the new medication is a depot, in some circumstances (e.g. risperidone and aripiprazole long-acting injectable) the oral medication needs to be continued past the initiation of the depot, as the latter takes a few weeks to establish therapeutically efficacious levels.

6. Clozapine is the antipsychotic of choice for treatment resistant patients (A).
It should be used if at least 2 other antipsychotics given in sufficient doses (see above) and duration (at least 4 weeks) have failed (C).

﻿Justification:

Clozapine has been shown to be significantly more efficacious than first-generation antipsychotics for treatment resistant patients in single RCTs and meta-analyses (Kane et al., 1988; Leucht et al., 2009b; Rosenheck et al., 1997; Wahlbeck et al., 1999). Although the evidence compared to second-generation antipsychotics is less clear (Leucht et al., 2009d), it remains the drug of choice for these people. The recommendation that at least 2 other drugs should have been used before clozapine is started is a pragmatic one doing justice to the increased risk of agranulocytosis and related increased blood test requirements, as it is implemented in most labels.

7. Combinations of antipsychotics: No strong evidence supports the use of polypharmacy over monotherapy for efficacy (A-). A reduction of hyperprolactinemia when adding aripiprazole to haloperidol or risperidone and the reduction of body weight, lipid and glucose levels when adding aripiprazole to clozapine or olanzapine (but not when adding it to quetiapine or risperidone) has been shown (A).

﻿Justification:

Various systematic reviews have examined the effects of combining antipsychotic drugs. Most of them found a small, but statistically significant superiority of the combining antipsychotics, but the evidence was never convincing. Correll et al., 2009b meta-analysed all combinations of antipsychotics irrespective of the drugs used. Combination therapy was more efficacious than monotherapy, but the effect was mainly driven by Chinese trials, in which combination treatment was given right from the start, rather than only in the case of non-response. Three other systematic reviews specifically examined combinations of clozapine plus another antipsychotic: Sommer et al., 2011 who analysed each antipsychotic added to clozapine separately found only sulpiride augmentation to be effective, but this finding was based on a single trial. Taylor et al., 2012 analysed all antipsychotics added to clozapine as one group and found a small but statistically significant superiority of the combination strategy. In another meta-analysis by Barbui et al., 2009, the same combination strategy was, however, only superior to clozapine monotherapy in open RCTs, but not in double-blind ones. In choosing an antipsychotic that is added to clozapine, it might be considered that clozapine has a low affinity to dopamine receptors. Therefore, drugs that are selective for dopamine receptors, such as amisulpride or sulpiride, but also aripiprazole (mainly a partial dopamine agonist) or risperidone or haloperidol, may be more reasonable choices than adding another multi-receptor antagonist, but we emphasize that this theory based on receptor binding is very weak. Another pragmatic aim should be to avoid additive side effects in particular weight gain, orthostatic hypotension and anticholinergic load.

However, although we do not recommend antipsychotic combination treatments and these are generally associated with the risk for increased adverse effects, some isolated combinations have been associated with specific reductions in adverse effects in open label as well as randomized controlled trials (Gallego et al., 2012). This includes the reduction of hyperprolactinemia and amenorrhea when adding aripiprazole to haloperidol or risperidone and the reduction of body weight, lipid and glucose levels when adding aripiprazole to clozapine or olanzapine (but not when adding it to quetiapine of risperidone).

8. Combinations of antipsychotics with other drugs: There is no evidence that would strongly support the use of any adjunctive agent for refractory positive symptoms (C). Adjunctive agents might be used for their target symptoms (e.g. benzodiazepines for sedation and anxiety, anti-manic drugs for manic symptoms, at best, knowing that even the evidence for such indications is extremely limited (C).

﻿Justification:

Numerous augmentation strategies that have been examined to improve the positive symptoms of schizophrenia, but there was no clear effect of benzodiazepines (apart from sedation, (Dold et al., 2012)), beta-blockers (Cheine et al., 2003), lithium (Leucht et al., 2007b), carbamazepine (Leucht et al., 2007c) and valproate (Basan and Leucht, 2004). The largest valproate study (249 participants) showed a more rapid onset of improvement in the augmentation group at two weeks (Citrome et al., 2004), but even this effect was not replicated in another trial with 402 participants (Casey et al., 2009). Lamotrigine is a promising adjunct, but the results on each efficacy outcome in a Cochrane review were only based on two studies (Premkumar and Pick, 2006), and lamotrigine’s superiority in meta-analyses restricted to clozapine non-responders was driven by an outlier (Sommer et al., 2011; Tiihonen et al., 2009, also see below). Moreover, the latter meta-analyses were relatively small and possibly not robust (Trikalinos et al., 2004). The effects of other augmentation strategies, such as polyunsaturated fatty acids (Omega-3 and Omega-6 fatty acids (Joy et al., 2006), glutamatergic agents (Tuominen et al., 2006), estrogens (Chua et al., 2005), dehydroepiandrosteron (DHEA) (Elias and Kumar, 2007), amphetamines (Nolte et al., 2004), cyclooxygenase-2(COX-2) inhibitors such as celecoxib (Akhondzadeh et al., 2007) and erythropoietin (Ehrenreich et al., 2007) are either still in the experimental stage or inconclusive. In their meta-analysis of five trials Sommer et al., 2012 found a significant effect of adding non-steroidal anti-inflammatory drugs to antipsychotics, but they could not include a large unpublished trial that contained more patients than all 5 included studies together that showed no significant effects (Rappard and Müller, 2004). Therefore, adjunctive agents might at best be used for their target symptoms, e.g. benzodiazepines for sedation or mood-stabilisers for severe manic symptoms, keeping in mind that the evidence is even more limited, because many studies did not even address these target symptoms.

Concerning more information on the effects of adjunctive agents on specific symptoms, such as depression, negative symptoms or cognitive dysfunction, see below.

Evidence for efficacy of augmenting clozapine is currently scarce. In a systematic review that analysed each adjunct individually (for example all antipsychotics added to clozapine were analysed individually rather than as one group) only adding lamotrigine or topiramate was associated with higher efficacy than placebo, but both results were driven by single outlier studies (Sommer et al., 2011). A meta-analysis on adding another antipsychotic to clozapine in non-response that pooled all antipsychotics as one group found a small but statistically significant superiority of the combination strategy (Taylor et al., 2012), but it left it unclear which combination is beneficial. In another meta-analysis by Barbui et al., 2009, the same combination strategy was, however, only superior compared to clozapine monotherapy in open RCTs.

In choosing an antipsychotic that is added to clozapine, it might be considered that clozapine has a low affinity to dopamine receptors. Therefore drugs that are selective for dopamine receptors such as amisulpride or sulpiride, but also aripiprazole (mainly a partial dopamine agonist), risperidone or haloperidol are more reasonable choices than adding another multi-receptor antagonist. As the evidence for these strategies is scarce the avoidance of additive side effects is another important goal. In this context, randomized controlled data may warrant consideration showing that aripiprazole augmentation of clozapine was associated with significant reductions in body weight and fasting glucose and triglyceride levels, even when keeping the clozapine dose stable (Zhang et al., 2010).

10. ECT may be considered as a last resort (A).

﻿Justification:

The evidence of ECT in treatment resistant patients is very limited. Tharyan and Adams, 2005 found a significant superiority of adding ECT to antipsychotics which was based only on a single small trial. But as ECT has a different mechanism of action than antipsychotic drugs, it may be considered as a last resort if all other attempts have failed. Moreover, a recently published randomised, open trial showed a clear advantage of clozapine non-responders who received ECT (Petrides et al., 2015). It is well possible that this trial changes the overall results of the Cochrane review once it has been updated.

11. If adding and antipsychotic or other adjunct was not effective, it should be tapered off (C).

As summarized above, the evidence of all combination strategies is limited. If such a combination is still tried, the response should be assessed and if it was ineffective it should be stopped to avoid side-effects, drug-drug-interactions and unnecessary cost.